This project is directed at delineating the cellular and molecular mechanisms of the immunopathogenesis of HIV infection. Using the chronically infected T cell (ACH-2) and promonocytic (U1) cell lines we have made a number of observations. The endogenous cytokines tumor necrosis factor alpha (TNF-alpha) (in ACH-2) and TNF-alpha, interleukin (IL)-6, and granulocyte-macrophage colony stimulating factor (GM-CSF) (in U1) can potently upregulate HIV expression. TNF-alpha induces HIV expression in an autocrine and paracrine manner, while IL-6, GM-CSF, and TNF-alpha synergize in HIV induction in U1 cells. TNF-alpha acts by inducing new transcription via an NFkB mechanism, while IL-6 and GM-CSF either alone or in combination act by post-transcriptional mechanisms. The pleiotropic cytokine transforming growth factor-beta (TGF-beta) downregulates the induction of HIV by phorbol myristate acetate (PMA), IL-6, and GM-CSF, but not by TNF-alpha. Glucocorticoids (GC) are post-transcriptional synergistic co-inducers with IL-6, GM-CSF, and interferon (IFN)--gamma of HIV expression in U1 cells. Heat shock (42 degrees C) alone induces HIV expression by increasing transcription from the HIV-LTR and physiologic heat (40 degrees C) synergizes with IL-6, GM-CSF, or GC in the induction of HIV expression. Activated B cells from HIV-infected individuals constitutively produce increased amounts of TNF-alpha and IL-6 and are capable of inducing HIV expression in U1 and ACH-2 cells in co-culture or via supernatants. We have shown that the reservoir of HIV infection in the peripheral blood is the CD4+ T cell. Also, there is a direct correlation between viral burden, depletion of CD4+ T cells and disease progression. HIV preferentially infects the memory subset of CD4+ T cells. HIV infects intrathymic T cell precursors which may explain the inability to completely regenerate CD4+ T cells even during effective anti-retroviral therapy. There is a progressive and preferential loss during the course of HIV infection of HIV-specific CD8+ cytolytic function as opposed to broad cytolytic potential. We have demonstrated that CD8+ T cells can be infected with HIV in vitro by direct contact with infected CD4+ cells. We have also demonstrated the presence of in vivo infected CD8+ cells. Leukocyte adhesion molecules, particularly LFA-1 are involved in the cell to cell spread of HIV, and this spread can be blocked by antibodies to these molecules.